Emerging Immunotherapy Options for CLL

Published on
February 26, 2016

Topics include:
Treatment

With all the emerging
immunotherapy options for CLL patients, it is difficult to know and understand
what they do and how they work. CLL
experts Dr. Zeev Estrov, Dr. Michael Keating and Dr. Nicole Lamanna discuss the
strategies of various checkpoint inhibitors and CAR-T cell therapies and how
they work in a balancing act between both suppressing and stimulating your
immune system.

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Andrew Schorr:

So in development,
so Dr. Estrov, do you want to talk about any of this; what’s in development
now?

Dr. Estrov:

Clearly the immune
system can control the disease since a part of the immune system can kill CLL
cells. So how can we putthe immune system to work? One of the drugs that is out there and is not
approved yet is lenalidomide (Revlimid).

Andrew Schorr:

It’s used in
multiple myeloma, another cancer.

Dr. Estrov:

Lenalidomide is a
drug that’s used profoundly in multiple myeloma; almost every multiple myeloma
patient receives it as part of his therapy at one point or another. But it has activity in CLL.

And there are patients with
CLL that respond to it. Although they
don’t go into remission; even when you stop the drug, still the response can
last for several years. Why? Because it modifies the immune system, the
other modifiers of the immune system, and there are two categories or
classes. One is checkpoint
inhibitors. What is a checkpoint
inhibitor?

So there are immune cells
that are called T lymphocytes. A subset
of T lymphocytes called CD8 cells can attack and kill CLL cells. But they fail to do it at one point in time
for two reasons. One is that they don’t
attach very well to the CLL cells. And number
two is that over time, they get overworked; they get fatigued and they expressall kinds of proteins that we find in
fatigued cells. In other words, they run
out of gas. So how can we fix it? How do neoplastic cells protect themselves
from these CD8 cells? They produce, on
the surface, proteins that prevent the interaction between the T lymphocytes
and the CLL cells, the cancer cells.

And when we attack these
protective proteins with antibodies, suddenly the T lymphocytes can do their
job. This is called checkpoint
inhibitors, and there are several of them.
They are effective in other cancers like metastatic melanoma, to which
effective treatments were not available and these patients are doing now much
better; at least 20 percent of them.

Andrew Schorr:

Lung cancer, as
well.

Dr. Estrov:

Lung cancer is one
of them, and in other neoplasms we see it, as well. We have now clinical trials in patients with
CLL. Another strategy is to generate
cells in the laboratory that are called cells that have chimeric antigen
receptors.

So they express in a way
antibodies that can identify the CLL cells and they are inherently T
lymphocytes so they can kill the CLL cells.
This strategy was discovered many years ago by a scientist in the
Weizmann Institute in Israel, named Zelig Getrall. And in recent years it started to be
introduced into clinical trial and given to patients with all kinds of
neoplasms, including CLL.

Andrew Schorr:

Let me just
mention, some people saw—there was a big front page article in the New York Times a few years ago where
some people were near death with CLL.
And this strategy was used to basically make a drug for them, a
customized drug in the lab and then re-injected. And they survived. Most of them survived. And some of them had remarkable turnaround.

Now, with these checkpoint
inhibitors, I can tell you there are people that I've met who are near death in
lung cancer and melanoma. And one lady I
met, incredibly now is playing golf three days a week, when she was near
death. So the question is, does this
supply to a blood cancer, CLL, and the CAR-T cell area has been very expensive
to produce. How do they do it? And then if they can figure out how to do it,
in not a super customized way but a way, still, that’s right for you. Who needs
it, and how do they also manage the immune system so that it doesn’t overreact? Because you’re turning up the immune system,
turning up the blast but not too much, right?

Dr. Keating:

The whole concept
is how can you get the immune T lymphocytes to have an effective intercourse
relationship with a malignant cell. So
you have to actually get it in close proximity, get the right adhesion. The way that T cells kill of foreign cells—and
their job is not just to kill off cancer cells.
But, for example, the rejection of a kidney transplant is you put in a
foreign kidney, and the T cells go and they say: hey, this is not my kidney, so
my job is to get rid of it. So they
stick to it, and they squirt enzymes into the kidney cell and blow it apart.

So you have to suppress that
immune system for the kidney to survive.
Over years, the CLL cells are foreign, and they’ve been attacked by the
T cells, as Dr. Estrov said. A number of
the malignant cells keep on getting killed.
But the survivors are playing tricks as to how to obey that
mechanism. And it’s like the T cells
send out these little tentacles,and
the surviving CLL cells send out neutralizing chemicals. So they get all
tangled up. So the T cell can’t move
around and do its thing. So you're in
the chapel of academia at MD Anderson.

There’s a guy here, Jim Ellison,
who is going to win the Nobel Prize probably in the next two years, because he
developed the first checkpoint in ibida.
And this led from malignant melanoma with zero percent five-year
survivors up to 20 percent. Then you add
this other one, nivolumab (Opdivo) and it gets up to about 40 percent in the
lung cancer. But we weren’t allowed to
work in the leukemias, because the companies that make it didn’t have very much
experience in leukemias, and they were a little bit scared it would mess up
their drug development. So he developed
an antibody that would attach to thesecells
and open them up.

So the T cell had room to
move. And now there are a whole bunch of
“me, too” type things that are looking at both sides of how you can neutralize what’s
happening in the cancer cell and what’s happening in the immune cell. And it’s a much easier thing to do than doing
the CAR-T cells, because we’re using your own cells. The drug is already there, so you don’t have
to go to the lab and expand everything up, etc.
So it’s an off-the-shelf type approach that is heavily into treatment at
the present time.

Dr. Lamanna:

I just want to say
one thing. But you could see how
therapies evolve. So when folks like Dr.
Keating and then us younger folks joined in, essentially we thought that just
attacking the B cells was enough. But
that clearly wasn’t enough, right? So we
were harming good cells, and we were trying to kill off these malignant B cells.
And you can see that there are so many other cells, as he alluded to as well;
all these other immunomodulatory cells, T cells and regulatory cells; there’s
so much that impacts the survival of the CLL cells. It is not just the CLL.

And that’s why you could see
these evolving trends over time of looking at different strategies to help kill
obviously the cancer cells but also some of the supporting cells that may
contribute to why we haven’t been successful in eradicating this fully.

And so it’s a lot more
complicated but very important as we delve into new therapies. And as they both alluded to, it’s a fine
balancing act. Because now we’re
stimulating the immune system, we’re suppressing the immune system, and it may
cause other complications. And so we’re
all going to have to, as we move forward in this new area, we’re going to have
to balance all these things together.
Fair?

Dr. Keating:

Yes.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.